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Tissue Biomarkers in Oncology
Clinical Development
The Digital Advantage
Christopher Ung
VP Strategic Business & Operations, Oncology
TMD – A Quintiles Laboratory
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The Targeted Therapy Continuum
Non-Targeted
Targeted (Somewhat)
Personalized Med.
(bcr/abl)
Chemotherapies
(c-kit)
(EGFR)
(KRAS)
(HER2)
(PDGFR)
Erbitux
Vectibix
(HER2)
(pHer2)
(pHer3)
Herceptin
Gleevec
Iressa
Erbitux
Tykerb
1998
2002
2003
Time Consuming
Clinical Endpoints
(TTP, OS)
Earlier decisions based
on Biological Endpoints
“More is better”
(MTD Approach)
Efficacy without
Toxicity (Biologically
Effective Dose)
No target
population
Targeted Population
2008
2008
Biomarker-Driven
Single or Combination
Therapy
Treat Based on
Treat Based on “some”
Treat Based on Molecular
Histology
Biomarkers
Profile
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Predictive Biomarkers for Response To
Lapatinib
Arm A Biomarker Analysis
Pre-Treatment
Post-Treatment
Observations of Predictive Biomarkers:
•Most patients in Cohort A (HER2
overexpressing) had high p-HER2
•However, co-expression of p-HER2 AND
p-HER3 predicted for response to
lapatinib
•High IGF-1R expression does not appear
to play a role in drug resistance, nor does
PTEN deficiency
Johnston, et al. (2008). Phase II Study of Predictive Biomarker Profiles for Response Targeting Human HER-2
in Advanced Inflammatory Breast Cancer With Lapatinib Monotherapy. JCO 26(7): 1066-72.
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Quintiles – Solid Tumor Oncology
Services
 Biomarker Driven
 Spans Discovery
through Clinical
Development for
Oncology
 Science Differentiator
CAP
CLIA
GLP/GCP
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Our Biomarker Tool Set
FFPE Tissue
Immunohistochemistry (IHC)
Immunofluorescence (IF)
Tissue Microarray (TMA)
Fluorescent in situ
hybridization (FISH)
Chromogenic in situ
hybridization (CISH)
Xenografts
Digital Pathology &
Image Analysis
Frozen Tissue
Real-Time PCR (Mutation
Analysis & Gene
Expression)
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Biomarkers for Oncology Drug
Development: An Example
Biomarkers to Analyze “Activation” Status of PI3K Pathway
 PI3KCA mutation, PI3KCA amplification
 PTEN expression by IHC (advantages over sequencing)
Other Biomarkers
 KRAS and/or BRAF mutation (depending on tumor type)
 EGFR, HER2, c-Met amplification (depending on tumor
type)
 IGF-1R, p-EGFR, p-HER2, p-HER3
Biomarkers for PD/Target Modulation
 p-S6, p-4EBP1, p-mTOR, Cleaved Caspase 3, Ki67
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The Challenges of IHC
IHC is subjective Hard to move tissue
in and out of China
Interpretation
Turnaround time
between
pathologists can be and cost can be
high if testing is
inconsistent
“over-centralized”
Non-numerical
biomarker
representation is
difficult to use
Broken Slides
Lost Slides
Expensive to
ship
Images are hard to
transmit
Outsourcing to
independent labs is
tricky especially
with data
integration
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Quintiles Labs Global Coverage
Edinburgh
Scotland
Beijing
China
QWES Chicago
Atlanta
United States
Mumbai
India
Singapore
Sao Paulo
Brazil
Owned Facility
Anatomic Pathology
Support
Services
Buenos Aires,
Argentina
Pretoria
South Africa
Affiliated Facility
Regional Labs Allow for Rapid TAT and Lower Shipping Costs
Tokyo
Japan
Tissue Biomarker Assay Development
Model
 Proof or Robustness. Full
development & validation
at TMD.
 SOPs in place
 Teams trained at TMD
 Both platform and
technology are reviewed
 Performance qualification
at global labs
 TMD inspects global labs
 Extensive use of digital
pathology platform to
maintain quality and
consistency
Develop Centrally, Perform Globally
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IHC Assay Validation with Image
Analysis
LNCap
PC3
DU145
ZR75-1
T47D
MWM
MCF-7
Stroma
Tumor
T47D (Wild-type PTEN)
No tumor PTEN staining, high stromal cell
staining
PTEN
Actin
Stroma
Du145 (1 Wild-type Allele, 1 Mutant Allele)
Tumor
Moderate tumor PTEN staining, high stromal cell
staining
PC3 (PTEN Homozygous Deletion)
Numerical Data May Enable Further Resolution in Analyses
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 Multi-site Integration in a Global
Environment
Multisite Integration in a Global
Environment
Pete Tearle
Sep 15. 7:00 pm – 9:00 pm
Atlanta Room
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Quintiles Digital Pathology Applications
for Drug Development
 Image Analysis & Technology Transfer for Image
Analysis Algorithms
 Collaboration & education – Digital Pathology
conferencing
 Global review of tumor presence prior to genotyping of
solid tumors
 Simultaneous biomarker review of patient data
 Tissue Micro Array and Cell Micro Array analysis
 Digital Slide Scanning
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www.quintiles.com/centrallab
www.quintiles.com/centrallab
Quintiles Global Oncology Laboratories
 CAP, CLIA, GLP, GCP Laboratories
 Anatomic Pathology Services







Basic anatomic pathology (accessioning, microtomy,
processing, H&E)
Immunohistochemistry (common signaling pathways),
HER2 FISH , EGFR FISH
Mutation analysis (Real-Time PCR)
High resolution scanning of images (Aperio
ScanScope)
Tissue MicroArray prep, staining and reporting
Biorepository
 Experienced Quintiles histotechnologists
 Dual platform – DAKO + Ventana
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Leveraging Digital Pathology for the
Development of Targeted Therapies
 Invest in a standardized system for global deployment
 Use the platform to increase collaboration and learning,
internally and with key constituents
 Engage the benefits of archiving, secure back up, image
management and image retrieval
 Use tools such as TMA Lab and image analysis algorithms
to create assay development value
 Obtain input for additional creativity and solutions
 Stay strong in the vision
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